抗心律失常課件

1、抗心律失常課件抗心律失常藥抗心律失常藥Anti-Arrhythmic Drug抗心律失常課件正常心臟電生理正常心臟電生理抗心律失常課件Cardiac electrical activity and ECG抗心律失常課件 Cardiac electrical activity抗心律失常課件Heterogeneous APs in heart抗心律失常課件Ion channels and AP01234INaICa.LIKrIKsIK1IK1ITo1INa-Ca抗心律失常課件Ion currents underlying AP in ventricleInward currentsInward c

2、urrentsI INaNaI ICaCaI INaNa/CaCaOutward currentsOutward currentsI IK1K1I Ito1to1I IKrKrI IKsKsI Ito2to2I ITOOSCN5ASCN5ADHP receptorDHP receptorNCX1NCX1Kir2Kir2.x xKv4Kv4.x x?HERGHERG/MiRP1MiRP1KvLQKvLQT11/minminKKPossible clonePossible cloneTTX X, S STX X, lidocaine lidocaineDHPDHP, Cd Cd22+, Co Co

3、22+ NiNi+, NCX1 NCX1-antibodantibodyBaBa22+44-APAPDIDSDIDS, 9-ACACDofetilideDofetilide, sotalol sotalolChromanol 2Chromanol 293B3BBlockersBlockers抗心律失常課件竇房結(jié)細(xì)胞動(dòng)作電位時(shí)程中的參與電流竇房結(jié)細(xì)胞動(dòng)作電位時(shí)程中的參與電流（Currents underlying depolarization in SA nodal cells）抗心律失常課件心律失常發(fā)生機(jī)制心律失常發(fā)生機(jī)制折返折返自律性升高自律性升高后除極后除極 早后除極早后除極 遲后除極遲后

4、除極基因缺陷基因缺陷抗心律失常課件折返形成機(jī)制折返形成機(jī)制(Unidirectional block and reentry)抗心律失常課件預(yù)激綜合癥中房室預(yù)激綜合癥中房室折返環(huán)路的形成折返環(huán)路的形成Atrioventricular reentry in the Wolff-Parkinson-White syndrome抗心律失常課件心肌細(xì)胞的早后除心肌細(xì)胞的早后除極和遲后除極極和遲后除極(Two forms of abnormal activity, early and delayed afterdepolarizations)抗心律失常課件抗心律失常藥物作用抗心律失常藥物作用降低自律性降

5、低自律性減少后除極減少后除極消除折返消除折返抗心律失常課件降低自律性的降低自律性的四種方式四種方式(Four ways to reduce the rate of spontaneous discharge in automatic tissues)抗心律失常課件心律失常類(lèi)型心律失常類(lèi)型抗心律失常課件Atrial flutter 抗心律失常課件Atrial fibrillation抗心律失常課件Atrial fibrillation抗心律失常課件Ventricular beat抗心律失常課件Ventricular fibrillation抗心律失常課件Cardiac arrhythmias T

6、achy-cardiac arrhythmias -Atrial-premature beats-Atrial flutter-Atrial fibrillation (AF)-Ventricular-premature beats (contractions)-Ventricular-tachycardia (VT)-Ventricular fibrillation (VF)Brady-cardiac arrhythmias-Bundle branch blocks-Sinus bradycardia (Sick Sinus Syndrome) 抗心律失常課件抗心律失常藥物分類(lèi)抗心律失常藥物

7、分類(lèi)抗心律失常課件Summary of antiarrhythmic drugsClassDrug exampleActions UsesIaIbIcQuinidine, ProcainamideLidocaine, MexiletineFlecainide, EncainideBlock of INa, IK, and ICa, ADP, ERP, Velocity, ContractilityBlock of INa (fast dissociation), APD, ERPBlock of INa (slow dissociation), Velocity, ContractilityV

8、T, AFVP VTIIPropranolol, MetoprololBlock of -adrenoceptor ContractilityAT, VTIIIDofetilide, IbutilideAmiodaroneBlock of IKr, ADPBlock of INa (Inac), IKr, ADPAF, ATIVVerapamil, Diltiazem Block of Ca2+ channelsAPD, A-V velocityAFflutter抗心律失常課件End!抗心律失常課件Problems to be solved Pro-arrhythmias of antiarr

9、hythmic drugsi.e. lack of selectivity when they are used to treat atrial fibrillation. No effective drugs for arrhythmias in patients with heart failure. No drugs available for Sick Sinus Syndrome. 抗心律失常課件Pro-arrhythmia of antiarrhythmic drugs抗心律失常課件Arrhythmogenic action in rabbit heartQuinidine (5

10、M)E-4031 (0.5 M)Asono et al. (1997) JMCC,29:831 抗心律失常課件Lack of IKur in human ventricleAtrial cellVentricular cellA ControlD ControlB 4-AP 50 MC 4-AP-sensitiveE 4-AP 50 MF 4-AP-sensitive+50 50 mV200pA30 ms Li et al (1996): Circ Res 78:689抗心律失常課件Ion currents in human atrium & ventricleInward currentsO

11、utward currentsINaICaINa/CaIK1Ito1IKurIKrIKsAtriumVentricle抗心律失常課件Human atrial IKur-A target for developing selective anti-atrial fibrillation drug抗心律失常課件Atrial Fibrillation (AF) AF is the most common arrhythmia in elderly persons AF is a potent risk factor for ischemic stroke, increasing the risk o

12、f stroke 5-fold and accounting for about 15% of all strokes in USA. Symptomatic AF may also reduce quality of life, functional status, and cardiac performance. It is associated with higher medical costs as well as an increased risk of death.抗心律失常課件Go, A. S. et al. JAMA 2001;285:2370-2375.Projected N

13、umber of Adults With Atrial Fibrillation in the United States Between 1995 and 2050抗心律失常課件A population-based study of the long-term risks associated with atrial fibrillation 20-year follow-up of the Renfrew/Paisley study Stewart et al. Am J Med. 2002;113:359-64抗心律失常課件It is important to develop selec

14、tive anti-atrial fibrillation drugs抗心律失常課件Life-threatening VF in heart failure抗心律失常課件Heart failure-mortality15%Within 1 year after diagnosisKannel, et al. Br Heart J 1994;72:S3-S9抗心律失常課件80%In 6 years after diagnosisHeart failure-mortalityKannel, et al. Br Heart J 1994;72:S3-S9抗心律失常課件Of deaths, up to

15、 50% are sudden or unexpected50%Heart failure-mortalityTendera & Ochala Curr Opin Cardiol 2001;16:180 抗心律失常課件Lethal arrhythmias: VT or VFVFVT抗心律失常課件Prolongation of ECG Q-T interval in HF patients Choy et al. Am Heart J, 1998; 136:664-71抗心律失常課件Cellular mechanisms of arrhythmias in HFVTVTVFVFEADsContr

16、olHFDADsHF抗心律失常課件APs and Ito, IKs in dog ventricleLiu et alLiu et al. Circ Circ. Res Res. 1 1993;72:6713;72:671, 1 1995;76:3515;76:351抗心律失常課件Question How the heterogeneous electrophysiology of the transmural ventricular wall is remodeled in heart failure?抗心律失常課件Dog HF model and human HFHuman explant

17、ed heart抗心律失常課件Regional ventricular cells抗心律失常課件EndoM cellEpiEADsEADsEADsEADs in regional cells from dog HF抗心律失常課件No change of ICa in cells from dog HF AControlHeart failure- -50 mV0 mV500 pA100 msTP (mV)-3003060ICa (pA/pF)-9-6-30EndoMEpimV-40-200204060ICa (pA/pF)-9-6-30EndoMEpiBCControlHeart failur

18、e抗心律失常課件IK1 reduction in dog HFControlHeart failure 2 nA 100 ms- -40- -110 mVAB抗心律失常課件Reduction of regional IK1 in dog HFControlTP (mV)-80 -70 -60 -50 -40 -30Current (pA/pF)02468*HF-110 -90-70-50-30-30-20-10010HFControl* *TP (mV)Current (pA/pF)AB抗心律失常課件Reduction of regional Ito1 in dog HFTP (mV)-300

19、3060246810Epi M Endo ATP (mV)-3003060246810EpiMEndoControlHeart FailureB抗心律失常課件Down-regulation of IKs in dog HFEpiMEndoIKs.tail (+30mV)BCurrent (pA/pF)02468AControlEpiMEndoDEpiMEndo 400 pA 2 sec- -60+50mV-30IKs.tail (+30 mV)Current (pA/pF)02468EpiMEndoHeart failureC 400 pA 2 sec抗心律失常課件No change of I

20、Kr in dog HF+40 mVControlE-4031E-4031-sensitive +20 mV0 mV*I = 0A170 pA 1.3 sec+40 mV- -60- -30 TP (mV)-20 -10010203040IKr (pA/pF)0.00.81.0Epi M EndoEpi MEndoBControl:HF:抗心律失常課件抗心律失常課件No change of ICa in human HFTP (mV)-40-200204060Current (pA/pF)-12-10-8-6-4-20ControlHFABControlHF抗心律失常課件IK

21、1 reduction in human HFControlHeart failureCurrent (pA/pF)BTP (mV)-100-80 -60 -40 -20-18-15-12-9-6-303Control FH *ATP (mV)-80-60-40-200.00.51.01.52.02.5*抗心律失常課件Reduction of Ito1 in human HFATP (mV)-3003060pA/pF246810ControlFH*ControlHFB抗心律失常課件AControlHF250 pA1.2 sec- -50+50- -30BTP (mV)-30 -20 -10 010 20 30 40 500.00.8ControlHF*Down-regulation of IKs in human HF抗心律失常課件SummaryIKsIK1Ito1抗心律失常課件SummaryFibrillationVT0EADs抗心律失常課件IK1, IKs activatorsFuture p